Evidence for Positive Allosteric Modulation of Cognitive-enhancing Effects of Nicotine by Low-dose Galantamine in Rats

Overview

Journal Pharmacol Biochem Behav

Publisher Elsevier

Specialties Biochemistry
Pharmacology
Psychology
Social Sciences

Date 2020 Oct 6

PMID 33022302

Citations 2

Authors

Britta Hahn

Carolyn H Reneski

Malcom Lane

Greg I Elmer

Edna F R Pereira

Affiliations

Soon will be listed here.

Abstract

Cognitive-enhancing effects of nicotinic acetylcholine receptor (nAChR) agonists may be of therapeutic potential in disease states characterized by nAChR hypofunction; however, effects tend to be of small magnitude and unlikely clinical significance. The co-administration of a nAChR positive allosteric modulator (PAM) may enable larger effects by potentiating nAChR responses to an agonist. The acetylcholinesterase (AChE) inhibitor galantamine is a nAChR PAM at a low dose range. A recent clinical study testing effects of a single small dose of galantamine found evidence for synergistic effects with nicotine on one of several cognitive measures. In that study, residual AChE inhibition may have obscured interactions on other measures. The present study aimed at examining small galantamine doses devoid of AChE inhibitory activity in a rodent model of attention. The effects of galantamine (0.03-0.25 mg/kg s.c.) were tested in the presence and absence of nicotine (0.1 mg/kg s.c.) in rats performing the 5-Choice Serial Reaction Time Task, employing a within-subject factorial design. There were no effects on response accuracy of either nicotine or galantamine alone. However, the combination of nicotine and 0.06 mg/kg of galantamine significantly enhanced accuracy. AChE activity assays confirmed that, at this dose, galantamine was devoid of AChE inhibitory activity in the brain. The results suggest that cognitive-enhancing effects of nicotine may be potentiated or uncovered by an extremely small dose of galantamine, well below its typical therapeutic range in humans. Furthermore, these findings provide a general proof-of-principle for a nAChR agonist and PAM combination strategy for cognitive enhancement.

Citing Articles

Recent Advances in the Discovery of Nicotinic Acetylcholine Receptor Allosteric Modulators.

Manetti D, Dei S, Arias H, Braconi L, Gabellini A, Teodori E Molecules. 2023; 28(3).

PMID: 36770942 PMC: 9920195. DOI: 10.3390/molecules28031270.

Galantamine tethered hydrogel as a novel therapeutic target for streptozotocin-induced Alzheimer's disease in Wistar rats.

Rajkumar M, Sakthivel M, Senthilkumar K, Thangaraj R, Kannan S Curr Res Pharmacol Drug Discov. 2022; 3:100100.

PMID: 35510084 PMC: 9058960. DOI: 10.1016/j.crphar.2022.100100.

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